Several publications and patent documents are referenced in this application in order to more fully describe the state of the art to which this disclosure pertains. The disclosure of each of these publications and documents is expressly incorporated by reference herein.
One of the causes of skin darkening is the synthesis of melanin by cells known as melanocytes. Melanocytes synthesize melanin inside specialized organelles called melanosomes (reviewed in Orlow, 1998, in The Pigmentary System: Physiology and Pathophysiology 97, Oxford University Press, New York, Nordlund et al., eds). Melanosomes are formed by the fusion of two types of vesicles. Melanin is a dark biological pigment (biochrome) found in the skin, hair, feathers, scales, eyes, and some internal membranes of many animals that confers protection against ultraviolet radiation. Melanism refers to the deposition of melanin in the tissues of living animals, the chemistry of which depends on the metabolism of the amino acid tyrosine. More specifically, melanins are formed as an end product during metabolism of the amino acid tyrosine.
A particular problem that has been noted is the unwanted darkening of skin. This may result from a variety of causes, including skin conditions such as acne, and the application of certain topical compositions that cause such darkening as a side-effect. By way of example, such darkening is experienced from the application of certain deodorants or antiperspirants, or from other topical skin care products or topically administered medicaments.
While a variety of substances have been proposed for use as regulators of skin pigmentation, almost all of these substances work by either bleaching existing pigment or preventing new pigment synthesis by inhibiting the activity of tyrosinase, the principal rate limiting enzyme in the production of melanin. U.S. Pat. No. 6,123,959, for example, describes the use of aqueous compositions comprising liposomes and at least one competitive inhibitor of an enzyme involved in melanin synthesis. U.S. Pat. No. 5,132,740 describes the use of certain resorcinol derivatives as skin lightening agents. WO 99/64025 describes compositions for skin lightening which contain tyrosinase inhibiting extracts from dicotyledonous plant species indigenous to Canada. U.S. Pat. No. 5,580,549 describes an external preparation for skin lightening comprising 2-hydroxybenzoic acid derivatives and salts thereof as inhibitors of tyrosinase. WO 99/09011 describes an agent for inhibiting skin erythema and/or skin pigmentation, containing at least one carbostyril derivative and salts thereof. U.S. Pat. Nos. 5,214,028 and 5,389,611, describe lactoferrin hydrolyzates for use as tyrosinase inhibitory agents.
In WO 02 98347, Manga describes methods for identifying compounds that alter melanogenesis in melanogenic cells, more particularly, compounds that inhibit or enhance P protein function. This method is based, in part, on the observation that P protein function is required for proper cellular localization of tyrosinase and other melanosomal proteins, and is required for both full tyrosinase activity and melanogenesis in melanogenic cell types.
Orlow et al. describe screens for identifying compounds that inhibit or increase melanogenesis in melanogenic cells. See WO 01 1131. These studies were based upon the discovery that some compounds that inhibit melanogenesis do so by causing a mislocalization of tyrosinase, the key enzyme in melanin synthesis. Also, WO 2007/110415 is directed to the preparation of particular diacetyl trimers, and their use in compositions for cosmetic or therapeutic use, for decreasing melanin synthesis and concentration, for the lightening of skin.
The above disclosures are predicated on a method of action that proposes to modulate cellular activity, and that by doing so, would function to modify melanin content and thereby, the color or hue of the skin. The present invention focuses instead on the darkening that results from a variety of seemingly disparate origins, and seeks only to prevent such darkening, and not to modulate melanogenesis.
As described herein, the present invention addresses the need for novel agents that are capable of preventing the darkening phenomenon. Accordingly, the present invention provides compounds for use in skin care and personal care formulations, and corresponding methods for preventing hyperpigmented skin, undesired pigmentation disorder of skin, or undesired darkening of skin comprising administering such compounds, or formulations or compositions containing an effective amount of the inventive compounds.